CA2025498A1

CA2025498A1 - Bag filling method and apparatus for preparing pharmaceutical sterile solutions

Info

Publication number: CA2025498A1
Application number: CA 2025498
Authority: CA
Inventors: James A. Benn
Original assignee: Individual
Current assignee: Individual
Priority date: 1990-09-17
Filing date: 1990-09-17
Publication date: 1992-03-18

Abstract

ABSTRACT OF THE DISCLOSURE
A bag filling method and apparatus for preparing pharmaceutical sterile solutions in a plurality of sterile flexible bags in a non-sterile environment, which method and apparatus comprise providing a pre-sterilized tubular bag having a single inlet, introducing a solution through a sterilizing filter and introducing the sterile solution into the inlet of the tubular bag and sealing defined sections of the tubular bag after filling to a defined volume of the sterile solution to form a plurality of separate, flexible, sterile bags thereby providing a rapid, inexpensive, automated method and apparatus to prepare sterile solutions in bags.

Description

D~:SCRIPTlON

Bag Filling Me~hod and ~pl>aratu~ for Preparing Pharcaceutlcal Sterile 501ution3 Back~round of the Invcntion S It i9 desirable to provide a method and apparatus for packag~ng sterile solutions in pre-sterilized flexible bags to produce low C09t sterile bags of solutlon in a non-sterile field environment.
Generally, packaging machinery produces bags of solutions through filling preformed empty bags through a~ opening to each bag, and then saaling the opsning to produce a s0aled bag o~
solution. Steril~ bags of solution are oftan made through use oE pre-sterllizsd bags, where the packaging machinery plerces the bag to be filed in a sterile manner, po~sibly ln a ~terile atmosphere, to fill and seal the bag with sterile solution while maintaininy sterility of the solution and all internal bag surfaces. This method of making a bag of sterile solution requires use of a connecting methodology between bag set and filling machine that main~ains sterility ~f the fluid filling the bag and the interior of the bag set. For many purposes, this connecting methodology is not reliable enough to ensure steri~ity of the bags produced to a high enough level. For example, bags oE intravenous solutions Eor human use cannot be made this way because of the risk of contamination.
U.S. Patent 4,610,790, issued September 1986, hereby incorporated by r~ference, discloses a method and apparatus to ensure sterile Pilling of bags to a high enough lavel that the bags will be safe for containing intravenous fluids for human use. Individual bags oE sterlle solutlon are produced through u~ing a bag set consisting of 18 individual, flexible vinyl bags attached by means of tubing to a manifold containing 18 valves in turn attached to a sterillzing filter, all pre-sterlli~ed after assembly into a bag se~ at the factory where the bag set is assembled. I~he sterilizlng filter on the inlet to the bag set protects the internal volumes of the bag3 from contamlnatlon.
Individual sterile bags are produced in a non-sterlle field environment by filling each bag with solution through opening a single valve in the manifold, and Eeeding solution through the sterili~ing filt~r to the bag connected via the manifold.
Tubes leading to the filled bags are then sealed and cut to free the individual filled sterile bags from the manifold.
This method of producing bags of fluld i9 inadequate mainly because the co~ of the empty bag set is toolexpensive to make the cost of filled bags competitive with other methods of acquiring sterile bags of intravenous solution. The high cost of bag manufac~ure is due to the many tubes and connection3 that must be incorporated during manufacture oE the bags. Also, the configuration of the bag set does not lend itself to being ea~ily handled either manually or automatically.
It is therefore desirable to provide a new bag set design, method and apparatus that dramatically reduces the C05t and complexity of manufacture of the bag set, yet allows these bags to be filled to make sterile bags of solut~on easily and automatically in the field.
Summary of the Inventlon The invention relate~ to a bag set design, method and apparatu~ for preparinq bags of ster~le solution in a non-sterile environment.
The invention provides for a bag set de3ign and a method and apparatus for the use of the bag set in preparing small, flexible bags filled with a deEined volume of a pharmaceutical sterile solutlon, such as sterile water and sterile aqueous solutions, ~n a rapid, simple, automated and inexpensive manner.
The bag 3et i~ essentially a long, tubular, thermoplastic bag element, closed at one end, with a Eluid entry port on the other end connected by a single fill tube to a sterilizing fllter, f3 ~

all sterilized after assembly. During storage, transport and use, the sterllizing filter protects sterility of the interior of the bag. This single bag is used to make a plurality of smaller sterile bags o solutLon in the field through Eilling the ~ingle large sterile bag through the sterilizing ilter, then sealing off 9ection3 of the bag to form smaller sterile bags from the single large bag.
The method of the invention comprises providing a pre-sterllized flexible tubular bag set having a single inlet for the introduction of a solution to be packaged into small bags, the bag set typically any one of a thermoplastlc polymers, such as a heat-sealable, transparent, vinyl polymer. The method includes introducing the solution through a sterilizing filter into the single inlet of the bag set in a defined volume or weight, and thereafter sealing defined section3 oÇ the tubular bag set, typically by tran3verse sections, such a~ by the use of heat bars, radio frequency energy or ultrasonic energy to form small, flexible, sterilc bag~ o~ the st~rlle solution.
The sterilizlng filter may comprise any filter, but typically includes microporou3 filters having a pore size oE 0.50 microns or less. This method i9 unique, can be easlly automated and is inaxpensive and permits a high level o~ confidence in the sterility of the resulting bags oE sterile solution required ln pharmaceutical operations.
The bag set may be stored on a reel or other compact form for feeding to a Eilling station where the sterile solution ~s introduced. The filling operation may employ a weigh pan or a flow meter to meter a defined volume or weight of the sterile solution into the bag set prior to sealing the bag set to form the smaller bag. A sterile, ~ealed exit port may be inserted into the smaller bag and a bag hanging element added for ease in use of the bag.
The apparatus of the invention comprises a source of a tubular bag set to be filled with a sterile solution, such as in a continuous web form, the bag set having an inlet for the 2~$f~`g~ ' introduction of the sterile solution. The apparatu~ includes typically a qterilizlng filter ~o ~rovide a ~terlle solution into the bag ~et inlet and a ~illing ~tation and a ~ealing station for sequentially filling and sealing and means to advance the bag set from the source through the fllling and ssaling stations to provide smaller, sterile bags.
In Dne packaging apparatus, solution to be packaged is lntroduced from the source through a sterilizing filter into only the bag portion that ls removed from the source, e.g.
the reel, which portlon is pinched off to form a smaller bag, but leaves behind a tube that i8 still connected to the inlet of the bag set on the reel or bag set source. I~nother packaging apparatu~ and technique comprise initially only partia1 filllng of the bag set while it is still mounted on the bag set reel lS or bag set source and only wholly fillin~ the portion of the bag set after removal from the reel or source after which the filled portion ls then sealed. This apparatus and technique generally requires tho use of a spacer material for allow partial expanslon o~ the bag set portlon at it~ source to permLt flow of the sterile solution to the baq set. The apparatus and mathod includes the sequential filling and sea1ing of defined 3ections of the bag set to provide smaller bags of ~harmace~ically sterile solLutions .
The invention comprises an apparatus and method that provide for inexpensive and automated filling of many bags. In prior art techniques, the majority of manufacturlng co~t i5 added by the sterilizing filter and assembly of complicat~d maniEolds.
Additionally, these complicated manifolds can only be used manually, and qven then with great difficulty. The invention comprises an apparatus and a method to make many bags (mors than, say, 10 and up to, say, lO0) with a very simple bag arrangement and where a sing1e sterilizing filter can be used to fill many bags. Additionally, the invention gives the capability of assurlng a very high probability that each bag filled is sterile. The sterilizing filters can be tested at id t~
_ S _ the facility where they were made to assure that they are capable of sterilizing to a high probability level. These can then be assembled into the bag set, and the assembly ~terilized at the manufacturing facility, where quality assurance procedures can be used to show that sterilization wa~ effective for all bags. When the system is used in the field or hospital pharmacy to make bag3, the sterilizing filter again can be easily tested through the "bubble test" to determine that the sterilizing filter was actually performlng the sterilizing function during the bag fill sequence. In combination, all these quality asaurance steps can give the user in the pharmacy the assurance that le6s than one bag in a million will be ~ot sterile. This i~ the same level of assurance the FDA now requ~res for all medical solutions.
The invention will be described for the purpose oF
illu~tratlon only ln connection with certain embodlment~ to be described; however, it is recognized that thoæe per~ons skilled in the art may make various changes, additions, modifications and improvemen-ts in the illustrated embodiment~, all falllng wlthin the spirit and scope of the invention.
Drie Descriptio~ GE the Drawings Fig. 1 i~ an lllustrative top plan view of a bag set used in the invention;
Fig. 2 is an illustrative, enlarged top plan view of a full slngle bag formed from the bag set of Fig. 1J
Fig. 3 18 an enlarged, fragmentary, illustrative view of the exit port of the bag of Fig. 2;
Fig. 4 is an illustrative top plan view of another bag set used in the invention;
Fig. 5 is an illustrative top plan view of a plurality of slngle bags formed from the bag set of Fig. 4;
Fig. 6 is a schematic, lllustrative side vlew of a packaging apparatus u3ed to fill the bag sets of Fig l;
Fig. 7 ls an enlarged, cross-sectional view of the bag set of Fig. 6 on a reel;

Fig. 8 is another enlargecl, cross-sectional view o~ the bag set of Fig 6 with a spacer:
Fig. 9 is an illustrative to~ ~lan vie of th~ packaging apparatus of Fig 6;
Fig. 10 is an illus~rative top plan vlew of another bag set used in the inventlon:
Fig. ll is a schematic, illustrative slde view of a packaging apparatus used to fill the bag ~et~ of Fig lO; and Flg. 12 is an lllustrative top plan view of the packaging apparatu~ of ~ig. 11.
~rief Dcscription of the ~mbodiment~
F~g. 1 show9 the ba~lc low cost bag sst deslgn o~ the invention. The set is essentially one large bag l attached ~o~ ~ ~ , a fill tube 2, which is in turn attached to a 3terilizing filter ; 3¦~q 3. This large bag l can serve the dual purpose of a web that can be automatically fed into a packaging machine, and as bag feed ~tock which is filled with solution and segmented into individual bags in the packaging machine. This bag set configuration 1 can be made of a tube of vlnyl sealed at both ends, or can be made of two sheets oF vinyl sealed at all edges.
The interior of the vinyl material can be made buff or textured to prevent sticking of the two sides together during storage.
The whole bag l, fill~2 and filter 3 can be sterilized at the factory and remain sterile while stored and filled in the field.
~ig. 2 shows how the single, large bag 1 can be formed into smaller bags by means of heat or radio frequency (RF or ultrasonic~) sealing. After the sterile bag l is fi:Lled with ~terile solution, seals 4 are made in the large bag to made ind~vidual bags 4a, bag hanger provision 6 and spike entry port S. ~ag lab~ling 7 can be done at the factory or in the ield by a baq packaging machlne.
Fig. 3 show~ a close-up of a fluid exit port for the smaller bags 4a that can be made in the fleld by an RP or heat sealer that melt~ the vinyl bag material together. Vinyl patch 8 is attached to the outsld2 of the vinyl bag 4a during assembly at the factory. A weakened area 9 i3 present ln the patch to allow peel-back of that area. ~uring the heat seal ~roces~
in the field, seal line lO i3 formed. This produces a 1uid exit port wherain the flap 9 can be peeled back, expo~ing a 3terile surface ll to be punctured with a ~tandard intravenous ~olution zpike sst and a neck 12 through which the spike set enter~ the bag and whlch hold~ the splke set in place as the bag 4a is drained through the set.
Fig~. 4 and 5 show bag ~ets that are more expensive to fabricate than bag l, but are easier to fill and handle in the field. In Fig. 4 i~ shown partial bag partitions 13, bag labeling 14 and spike port 15 incorporated into the bag set in the factory.
Fig. 5 shows these features in addltion to bag hanging provision 16 and holes provlding for automated machine indexlng 17 by a bag packaging maciline incorporated into the bag set.
Fig. 6 shows packaging equipment that can be used to flll the bag~ described. A reel 18 holds the empty bag set wrapped on it for ~torage during the fllling operation. The sterilizing filter 3 i8 held at the center of the reel and provides entry for fluid into the bag set. The bag set is wrapped wlth spacers 19 to allow the set to expand enough to pass fluid from the entry port to the bag being filled 20. Bag 20 i9 positioned on a weight scale 21 or other fluid metering device during fllling to measure and meter volume into the bag being filled. Chamber 22 is evacuated partially to allow expansion of bag 20 to its specified ill volume. Fulcrum 23 allows the bag to be accurately weighted, and may provide a partial air seal for applying negative pressure on the walls of bag 20. The fulcrum 23 may also contain RF heating electrodes to apply sealing energy to the bag entrance, and act a~ a pinching device to effect the opening and closlng of the fluid entrance to the bag during filling. Positioning of the bag packaging ~tation below the storage reel allows gravity to assist in partially expanding the bags ~or filling.
Appropxlate indexing and bag transfer equipment tnot shown) are incorporated into the mechanism of Fig. 6 to allow mechanical ~ J ~ $
~8--and automated unreeling of the bag set and positionlng of the bag sets sequentially ~n the flll ~tation Eor Eilling and sealing and sub~equent removal of filled bags and insertion of the next bag to be filled.
Fig. 7 shows a cross sectlon of the bag wrapped on the reel 18 lncluding spacer 19 and bag set edge 24. ~ig. 8 shows another cross section of the bag with the spacer inserted and wrapped on reel 18~ The spacers l9 3eparate the bag set leave~
24 created by the spiral wrapping of the bag set on the reel.
Areas of the bag set 25 are not covered by spacers and are thus allowed to expand to permit fluid to flow along the length of the bag set from the filllng port to the bag being filled.
Fiq. 9 qhows a top vlew of the reel 18 and the bag set 24 unwinding from the reel to position the bag being filled 20 onto the weigh pan 21 for filllng in the vacuum chamber 22.
Sterili~ing filter 3 is positioned on the center of the reel ~or fluid entry into the bag set and subsequent f~lling of bag 20. 8terilizing filter 3 must b~ held 90 that the feed line to the filter can effect a rotating seal as the reel 18 i9 turned to unw~nd the bag set. Alternatively, sufficient tubing may be suppliQd 90 twisting of the feed line does not lnhibit fluid flow to the bag set.
In the above configurations, it is possible that the reel could be eliminated through proper packaglng of the empty bag ~et with associated spacers similar to spacer 19 to allow fluid to flow fxom the entrance of the set, through the set to the portion of the set being formed into bags. One example is where the bag set ls stored ln an accordion manner in a box. This storage technique would also eliminate need for a rotating seal on the entrance to the bag set.
Fig. 10 shows a variation of the bag set that allows a different type of filling sequence. In this case, the f~ll tube 2 enters the bag set web pro~er and continues the length of the bag set. Fluid connections 27 connect the ~naiv~dual bags 28 with the fill tube. This bag configuration allows a ~r;~
_9_ different type oE filling operatlon as shown in Fig. 11. Reel 18 holds the empty bag sat wrapped on it. The bag set 24 is rolled ofE the reel and fed onto the scale 21 and through the fulcrum and sealing jaws 23. In this case, the f~lllnq tube 2 enters the bag set web from the end where bags are being made.
Reel 18 can be replaced by a box holding the bags in a folded and compact manner sim~lar to a box holding a cont~nuous web of computer paper, as no fluld has to flow through the tubes as they are in the packaged position.
Fig. 12 shows a top view of the bag filling system. Reel 18 unrolls the bag set. The bags are sequentially place across the fulcrum and sealing edge 23 and filled Iby the fill tube 2. Fluid connection 27 also falls across the jaws of the fulcxum to provide for sealing of thc bag when it is filled to the proper volume. Once filled and sealed, bag 28 is cut or torn away from the bag set web to leave the fill tube 2 connectlng the next bag to be filled, for the sequence to be repeated. As this operation is repeated, fill tube 2 becomes longer and longer.
The ma~or difference between the filling sequence of Fig.
9 and that of Fig. 12 i8 that in the former, the bag set is filled from the opposite snd from which the bags are being made, and in the latter, the bag set i3 being filled at the same end the bags are being made. The advantage of both methods is that the bag set can be stored in a compact manner, yet fed into a single fill station which contains all the necessary valving and other equipment to fill, seal and separate the bags.
Additlonally, the bag set can be made as simple as in Fig. 1, and heat sealing equipment and labeling equipment can be incorporated at the filling station to make individual bags with spike ports and provision for hanging bags.
The advantage of the method shown in Fig. 9 is that the fill tube and associated passage~ from the fill port to the bag being filled are protected from kinks and ~03sible ~hysical damage during filling. Also, the removal of the filled bags 35 from the bag filling machine will be easier to automate and ea3ier for the operator to handle. Thi3 method could also be used to make, say, 100 bags Erom one bag sat. A disadv~ntage i8 the rotating seal or other means that must be incorporated between the fluid generation system and the sterili~ing Eilter to allo~ the reel to rotate to discharge bags to the bag filllng statlvn. With proper packaging, where the bags are stored in a foldea manner, but spassrs are still inserted to allow fluid fluld through the bags, th~ 5 disadvantage could be possibly ellminated.
The ndvantage of the method shown in Fig. 12 i8 that clearly the rotating seal or other rotating relieE means is eliminated from the system. Also~ better packing denslty may be achievsd with the empty bag sets, as spacers could be elimlnated between bags that were needed to provide for fluid flow through the bag set. A box for example could be used that contained the empty bag~ in a folded manner. A disadvantage is that the fill tube 2 become3 ~ncreasingly longer as the bag3 are filled, cau3~ng increased chance3 for klnking or physical damage to it during the flll cycle. Al30, the bag set wlll be more expensive to manufaature, calling for more sealing at the factory and po~sibly increaqed thickness of bag walls.
What is clai~ed ls:

Claims

Claim 1. A method of packaging a sterile solution into a plurality of sterile, flexible bags of defined volume in a non-sterile atmosphere, which method comprises:
a) providing a pre-sterilized bag set composed of a heat-sealable thermoplastic polymer, the bag set comprising a plurality of preformed, unfilled, individual bags of defined volume arranged in a sequentially connected series and adapted to be compactly stored in a unfilled condition, the bag set having a single inlet for the introduction of a sterile solution to be packaged and a single fill tube connected to the single inlet, the inlet tube extending generally the length of the bag set and a plurality of short, individual bag fill tubes extending from the single fill tube to each of the individual bags of the bag set;
b) compactly storing the bag set in a storage means;
c) sequentially withdrawing from the compactly stored bag set, the individual bags;
d) introducing a sterile solution of a defined volume into the single inlet of the bag set and through the fill tube sequentially into the individual fill tubes of the individual bags as withdrawn from the storage means;
e) filling a defined volume of the sterile solution from the fill tube and through the individual fill tube into the withdrawn individual bag as withdrawn from the storage means:

f) sequentially heat sealing the individual bag fill tube after the filling of the sterile solution; and g) removing from the bag set the individual, filled, sterile, heat-sealed, flexible bags.
Claim 2. The method of claim 1 which includes providing a bag set having individual bag fill tubes which extend at an angle from the single fill tube to an adjacent, offset individual bag and heat sealing the individual fill tube of the bag between individually separated bags.
Claim 3. The method of claim 1 which includes introducing a sheet of spacer material between the individual bags in the bag set in the compact, stored condition.
Claim 4. The method of claim 1 which includes compactly storing the bag set on a reel containing a spiral wound bag set and withdrawing individual bags from the reel as required for filling and sealing.
Claim 5. The method of claim 1 wherein the fill tube extends along one longitudinal edge of bag set and the individual fill tubes extend a short distance from the fill tube and at an angle of the fill tube.
Claim 6. The method of claim 1 which includes providing a bag set having bag hanging elements onto the individual bags of the bag set.
Claim 7. The method of claim 1 which includes providing a bag set having a sterile seal exit port in each individual bag of the bag set.
Claim 8. The method of claim 1 which includes filling the sterile solution into the individual bags withdrawn from the bag set to a defined volume by measuring the weight of the sterile solution introduced.
Claim 9. The method of claim 1 which includes introducing the withdrawn individual bag into a partial vacuum chamber containing a weighing device and providing for the expansion of the withdrawn individual bag in the vacuum chamber and filling the sterile solution into the expanded bag by weighing the sterile solution filled into the bag to a defined weight.
Claim 10. The method of claim 1 which includes introducing the sterile solution through a sterilizing filter into the single inlet of the bag set.
Claim 11. The method of claim l which includes:
a) storing the bag set between a layer of an adjacent spacer sheet material in a wound form on a reel;
b) connecting the single inlet of the bage set to a rotary seal at the center of the reel;
c) withdrawing sequentially the individual bags by unwinding the bag set from the reel;
d) placing the withdrawn bag onto a weighing pan for filling to the defined volume of sterile solution into the withdrawn individual bag; and e) introducing the sterile solution to be packaged into the rotating seal at the center of the reel on which the bag set is wound for filling into the individual bags.
Claim 12. The method of claim 1 which includes spirally winding the bag set onto a reel as the compact storage means and introducing the sterile solution into the single inlet of the bag set at the one end of the spirally wound bag set wherein the sequentially withdrawn individual bag is unwound from the reel for filling.
Claim 13. The method of claim 1 wherein the bag set comprises a transparent, heat sealable, thermoplastic polymer.
Claim 14. The method of claim 1 wherein the individual fill tubes extend at an angle from the single fill tube into the top on the individual bags and heat sealing the individual fill tube and between the individual bags in the bag set to permit removal of the individual heat sealed, filled bags from the bag set.
Claim 15. The heat sealed, removed, sterile filled, individual bags prepared in the method of claim 14.
Claim 16. A pre-sterilized bag set for use in a mthod of filling individual bags of the bag set with a defined volume of sterile solution, the pre-sterilized bag set composed of a heat sealable thermoplastic polymer, the bag set comprising a plurality of sequential, aligned, preformed, unfilled, separated, individual bags of defined volume, the bag set having a single inlet at the one end of the bag set for the introduction of a sterile solution to be packaged and a single fill tube connected to the inlet, the single fill tube extending along generally the entire length of the bag set, and a plurality of short, individual bag fill tubes extending from the single fill tube into each of the individual bags of the bag set.
Claim 17. The bag set of claim 16 which includes a sterilizing filter means comprising a microporous membrane filter with a pore size of not larger than about 0.45 micrometers secured to the single inlet of the bag set.
Claim 18. The bag set of claim 16 which comprises a transparent, heat sealble, thermoplastic vinyl polymer.
Claim 19. The bag set of claim 16 wherein the single fill tube extends longitudinally along the substantial entire length of one edge of the bag set.
Claim 20. The bag set of claim 16 wherein the individual fill tube extends a short distance and at an angle to the single fill tube.
Claim 21. The bag set of claim 20 wherein the angled individual fill tube extends opposite one individual bag of the bag set to the adjacent individual bag set so that heat sealing of the angled individual fill tube may also heat seal between the individual adjacent bags of the bag set.